Pyrimidine derivatives for the treatment of abnormal cell growth

ABSTRACT

The present invention relates to a compound of the formula 1 
     
       
         
         
             
             
         
       
     
     wherein A and Ar are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION(S)

Reference is made to U.S. Application Ser. No. 60/571,210, filed May 14,2004, the disclosure of which is incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

This invention relates to novel pyrimidine derivatives that are usefulin the treatment of abnormal cell growth, such as cancer, in mammals.This invention also relates to a method of using such compounds in thetreatment of abnormal cell growth in mammals, especially humans, and topharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane andpossess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. Otherreceptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr,and VEGFR. It is known that such kinases are frequently aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitor,selectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma that expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma that does not express the EGF receptor. Thus, selectiveinhibitors of certain receptor tyrosine kinases, are useful in thetreatment of abnormal cell growth, in particular cancer, in mammals. Inaddition to receptor tyrosine kinses, selective inhibitors of certainnon-receptor tyrosine kinases, such as FAK (focal adhesion kinase), Ick,src, abl or serine/threonine kinases (e.g., cyclin dependent kinases),are useful in the treatment of abnormal cell growth, in particularcancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2,PTK2.

Convincing evidence suggests that FAK, a cytoplasmic, non-receptortyrosine kinase, plays an essential role in cell-matrix signaltransduction pathways (Clark and Brugge 1995, Science 268: 233–239) andits aberrant activation is associated with an increase in the metastaticpotential of tumors (Owens et al. 1995, Cancer Research 55: 2752–2755).FAK was originally identified as a 125 kDa protein highlytyrosine-phosphorylated in cells transformed by v-Src. FAK wassubsequently found to be a tyrosine kinase that localizes to focaladhesions, which are contact points between cultured cells and theirunderlying substratum and sites of intense tyrosine phosphorylation. FAKis phosphorylated and, thus, activated in response to extracellularmatrix (ECM)-binding to integrins. Recently, studies have demonstratedthat an increase in FAK mRNA levels accompanied invasive transformationof tumors and attenuation of the expression of FAK (through the use ofantisense oligonucleotides) induces apoptosis in tumor cells (Xu et al.1996, Cell Growth and Diff. 7: 413–418). In addition to being expressedin most tissue types, FAK is found at elevated levels in most humancancers, particularly in highly invasive metastases.

Various compounds, such as styrene derivatives, have also been shown topossess tyrosine kinase inhibitory properties. Five European patentpublications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25,1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1(published Dec. 30, 1992), refer to certain bicyclic derivatives, inparticular quinazoline derivatives, as possessing anti-cancer propertiesthat result from their tyrosine kinase inhibitory properties.

Also, World Patent Application WO 92/20642 (published Nov. 26, 1992),refers to certain bis-mono and bicyclic aryl and heteroaryl compounds astyrosine kinase inhibitors that are useful in inhibiting abnormal cellproliferation. World Patent Applications WO96/16960 (published Jun. 6,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published Aug.21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (publishedJan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer tosubstituted bicyclic heteroaromatic derivatives as tyrosine kinaseinhibitors that are useful for the same purpose. In addition, thefollowing list of publications relate to bis-mono and bicyclic aryl andheteroaryl compounds that may optionally be used as tyrosine kinaseinhibitors: WO 03/030909, WO 03/032997, U.S. Patent Application No.2003/0181474, U.S. Patent Application No. 2003/0162802, U.S. Pat. No.5,863,924, WO 03/078404, U.S. Pat. No. 4,507,146, WO 99/41253, WO01/72744, WO 02/48133, U.S. Patent Application No. 2002/156087, WO02/102783, and WO 03/063794.

U.S. patent application Ser. No. 10/734,039, filed Dec. 11, 2003 relatesto a broad class of novel pyrimidine derivatives that are kinaseinhibitors, and more specifically, inhibitors of FAK. Moreover, U.S.patent application Ser. No. 10/733,215, filed Dec. 11, 2003 relate morespecifically to a subset of pyrimidine derivatives, i.e., those bearinga 5-aminooxindole, which are tyrosine kinase inhibitors, and moreparticularly, FAK inhibitors. Compounds such as these are useful in thetreatment of abnormal cell growth.

Accordingly, a need exists for additional selective inhibitors ofcertain receptor and non-receptor tyrosine kinases, useful in thetreatment of abnormal cell growth, such as cancer, in mammals. Thepresent invention provides novel pyrimidine derivatives that are kinaseinhibitors and inhibitors of the non-receptor tyrosine kinase, FAK, andare useful in the treatment of abnormal cell growth.

SUMMARY OF THE INVENTION

Therefore, the present invention provides a compound of the formula 1

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof,

wherein Ar is selected from:

and ring B is

wherein m is an integer from 0 to 2;

Ra represents substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy, —CF₃, —CN, —NR¹R², —OR¹, —R¹,—CO₂R¹ and —CONR¹R²;

Rb represents a substituent selected from the group consisting ofhydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—CO₂R¹, —CONR¹R²;

each Rc independently represents a substituent selected from the groupconsisting of hydrogen, halogen, hydroxy, —CF₃, —CN, —(C₁–C₆)alkyl,—NR¹R²,—OR¹, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹, and—CONR¹R² or two Rc substituents may be taken together with the atom(s)to which they are attached to form a cyclic group selected from—(C₃–C₁₀)-cycloalkyl and —(C₂–C₉)-heterocyclyl;

A is a suitably substituted cyclic moiety selected from the groupconsisting of (a) a —(C₂–C₉)heterocyclyl group inclusive of the ringnitrogen atom at the juncture between cyclic moiety A and the C-4position of the pyrimidine ring of formula I; and (b) a—(C₂–C₇)heterocyclyl group wherein two adjacent methylene carbons ofsaid —(C₂–C₇)heterocyclyl group are fused to a phenyl or—(C₂–C₅)heteroaryl group; wherein A is optionally substituted by 1 to 3substituents independently selected from the group consisting ofhalogen, hydroxyl, cyano, —R¹, —NR¹R², —NH(CO)R¹, —NR²(CO)R¹,—(C₁–C₆)alkyl-NR¹R², —(C₁–C₆)alkyl-NH(CO)R¹, —(C₁–C₆)alkyl-NR²(CO)R¹,—NHSO₂R¹, —N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹),—(C₁–C₆)alkyl(NHSO₂)(R¹), —(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —OR¹,—(C₁–C₆)alkyl-OR¹, —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂,SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionally interruptedby one to three elements selected from the group consisting of —(C═O),—SO₂, —S—, —O—, —N—, —NH— and —NR³;

R¹ and R² are each substituents independently selected from the groupconsisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉)heteroaryl; whereinsaid —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—(C₆–C₁₀)aryl, and —(C₁–C₉)heteroaryl R¹ or R² substituents areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, —CF₃, —CN,—(C₁–C₆)alkyl, —N H(C₁–C₆)alkyl, —N H(C₃–C₇)cycloalkyl,—NH(C₂–C₉)heterocyclyl, —NH(C₆–C₁₀)aryl, —NH(C₁–C₉)heteroaryl,—N((C₁–C₄)alkyl)₂, —N((C₃–C₇)cycloalkyl)₂, —N((C₂–C₉)heterocyclyl)₂,—N((C₆–C₁₀)aryl)₂, —N((C₁–C₉)heteroaryl)₂, —O(C₁–C₆)alkyl,—O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —O(C₆–C₁₀)aryl,—O(C₁–C₉)heteroaryl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, or

R¹ and R² may be taken together with the atom(s) to which they areattached to form an R¹, R² cyclic moiety selected from—(C₃–C₁₀)cycloalkyl and —(C₂–C₉)heterocyclyl, wherein said R¹, R² cyclicmoiety is optionally substituted by one to three elements selected fromthe group consisting of hydrogen, halogen, and hydroxy, and said R¹, R²cyclic moiety is optionally interrupted by one to three additionalelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR³;

R³ is a substituent selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,—(C₁–C₉)heteroaryl, —COR¹, and —SO₂R¹; wherein said —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl,—(C₁–C₉)heteroaryl, —COR¹, and —SO₂R¹ R³ radicals are optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁–C₆)alkyl,—NH₂, —NHR⁴, —NR⁴ ₂, —OR⁴, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—CO₂R, —CONH₂, —CONHR⁵, and CONR⁵R⁶; wherein R⁵ and R⁶ of —CONR⁵R⁶ maybe taken together with the atoms to which they are attached to form a—(C₂–C₉)heterocyclyl;

R⁴ and R⁵ are each —(C₁–C₆)alkyl; and

R⁶ is hydrogen or —(C₁–C₆)alkyl.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula 1, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically-labelled compounds of Formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily availableisotopically-labelled reagent for a non-isotopically-labelled reagent.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula 1. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,citrate, acid citrate, tartrate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula 1. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula 1 that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [, 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts. Thecompounds of the present invention that include a basic moiety, such asan amino group, may form pharmaceutically acceptable salts with variousamino acids, in addition to the acids mentioned above.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula 1. Compounds of formula 1 havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of formula 1. Theamino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters that are covalently bonded to the above substituents offormula 1 through the carbonyl carbon prodrug sidechain.

This invention also encompasses compounds of formula 1 containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula 1(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of formula 1 that can beseparated into rotationally restricted isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

The term “interrupted by” refers to compounds in which a ring carbonatom is replaced by an element selected from the group consisting of—(C═O), —SO₂, —S—, —O—, —N—, —NH—, and —NR³. For example, if asubstituent is —(C₆–C₁₀)aryl, such as

the ring may be interrupted or replaced by a nitrogen heteroatom to formthe following ring:

such that a ring carbon is replaced by the heteroatom nitrogen.Compounds of the invention can accommodate up to three such replacementsor interruptions.

Compounds of the present invention may include substituents, R¹ and R²,which may be taken together with the atoms to which they are attached toform a cyclic group, as defined above. In a preferred embodiment, suchcyclic groups will be formed when R¹ and R² are bound to the same atom,e.g., when R¹ and R² appear in the substituent, NR¹R², then R¹ and R²may be taken together with the nitrogen atom to which they are eachattached to form a cyclic group.

A “suitable substituent” is intended to mean a chemically andpharmaceutically acceptable functional group i.e., a moiety that doesnot negate the biological activity of the inventive compounds. Suchsuitable substituents may be routinely selected by those skilled in theart. Illustrative examples of suitable substituents include, but are notlimited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups,alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxogroups, mercapto groups, alkylthio groups, alkoxy groups, aryl orheteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl orheteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO—(C═O)—groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groupsdialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonylgroups, alkylsulfonyl groups, arylsulfonyl groups and the like. Thoseskilled in the art will appreciate that many substituents can besubstituted by additional substituents. Further examples of suitablesubstituents include those recited in the definition of compounds ofFormula 1, including those optional substituents of cyclic moiety A, asdefined hereinabove.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy), may be linear or branched(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl); optionally substituted by 1 to 3suitable substituents as defined above such as fluoro, chloro,trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁–C₆)alkyl. The phrase “each of said alkyl” as usedherein refers to any of the preceding alkyl moieties within a group suchalkoxy, alkenyl or alkylamino. Preferred alkyls include (C₁–C₆)alkyl,more preferred are (C₁–C₄)alkyl, and most preferred are methyl andethyl.

As used herein, the term “cycloalkyl” refers to a mono, bicyclic ortricyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bondsand optionally substituted by 1 to 3 suitable substituents as definedabove such as fluoro, chloro, trifluoromethyl, (C₁–C₆)alkoxy,(C₆–C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁–C₆)alkyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo oriodo or fluoride, chloride, bromide or iodide.

As used herein, the term “alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁–C₆)alkyl.

As used herein, the term “alkynyl” is used herein to mean straight orbranched hydrocarbon chain radicals having one triple bond including,but not limited to, ethynyl, propynyl, butynyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁–C₆)alkyl.

As used herein, the term “carbonyl” or “(C═O)” (as used in phrases suchas alkylcarbonyl, alkyl-(C═O)— or alkoxycarbonyl) refers to the joinderof the >C═O moiety to a second moiety such as an alkyl or amino group(i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refersto an alkyl carbamate group. The carbonyl group is also equivalentlydefined herein as (C═O). Alkylcarbonylamino refers to groups such asacetamide.

As used herein, the term “aryl” means aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indanyl and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicgroup usually with one heteroatom selected from O, S and N in the ring.In addition to said heteroatom, the aromatic group may optionally haveup to four N atoms in the ring. For example, heteroaryl group includespyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl),thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁–C₆)alkoxy, (C₆–C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁–C₆)alkyl.

The term “heterocyclic” as used herein refers to a cyclic groupcontaining 1–9 carbon atoms and 1 to 4 hetero atoms selected from N, O,S(O)_(n) or NR. Examples of such rings include azetidinyl,tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl,morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl,indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl,benzoxazinyl, and the like. Examples of said monocyclic saturated orpartially saturated ring systems are tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl,piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; optionally containing 1 or 2 doublebonds and optionally substituted by 1 to 3 suitable substituents asdefined above such as fluoro, chloro, trifluoromethyl, (C₁–C₆)alkoxy,(C₆–C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁–C₆)alkyl.

As used herein, “heteroaryl” and “heterocyclyl” may refer to monocyclic,bicyclic, spirocyclic, and tricyclic ring systems.

Nitrogen heteroatoms as used herein refers to N═, >N and —NH; wherein—N=refers to a nitrogen double bond; >N refers to a nitrogen containingtwo bond connections and —N refers to a nitrogen containing one bond.

“Embodiment” as used herein refers to specific groupings of compounds oruses into discrete subgenera. Such subgenera may be cognizable accordingto one particular substituent such as a specific Ar, Ra–Rc, and R¹–R⁶groups. Other subgenera are cognizable according to combinations ofvarious substituents, such as all compounds wherein R² is hydrogen andR¹ is (C₁–C₆)alkyl.

The compounds of the invention may contain Ar groups represented by

Compounds represented by this generic formula refer to fused bicyclicring systems wherein the aromatic ring adjacent to ring B bears one ormore nitrogen atoms in the ring. For example, such a structure may referto one or more of the following ring systems:

Therefore, the present invention provides a compound of formula 1wherein A is a suitably substituted —(C₂–C₉)heterocyclyl group inclusiveof the ring nitrogen atom at the juncture between cyclic moiety A andthe C-4 position of the pyrimidine ring of formula I; wherein A isoptionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of halogen, hydroxyl, cyano, R¹, —NR¹R²,—NH(CO)R¹, —NR²(CO)R¹, —(C₁–C₆)alkyl-NR R², —(C₁–C₆)alkyl-NH(CO)R¹,—(C₁–C₆)alkyl-NR²(CO)R¹ —NHSO₂R¹, —N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —OR¹, —(C₁–C₆)alkyl-OR¹,—(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²;and said cyclic group A is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR³.

The invention also provides a compound of formula 1 wherein A is asuitably substituted —(C₂–C₇)heterocyclyl group wherein two adjacentmethylene carbons of said —(C₂–C₇)heterocyclyl group are fused to aphenyl or —(C₂–C₅)heteroaryl group; wherein A is optionally substitutedby 1 to 3 substituents independently selected from the group consistingof halogen, hydroxyl, cyano, R¹, —NR¹R², —NH(CO)R¹, —NR²(CO)R¹,—(C₁–C₆)alkyl-NR¹R², —(C₁–C₆)alkyl-NH(CO)R¹, —(C₁–C₆)alkyl-NR²(CO)R¹—NHSO₂R¹, —N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹),—(C₁–C₆)alkyl(NHSO₂)(R¹), —(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —OR¹,—(C₁–C₆)alkyl-OR¹, —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂,SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionally interruptedby one to three elements selected from the group consisting of —(C═O),—SO₂, —S—, —O—, —N—, —NH— and —NR³.

The invention further provides a compound of formula 1 wherein Ar is amoiety of formula 2:

Also provided is a compound of formula 1 wherein Ra is selected from thegroup consisting of hydrogen, halogen, hydroxy, —CF₃, and —CN.Accordingly, the invention provides a compound of formula 1 wherein Aris a moiety of formula 2 and Ra is selected from the group consisting ofhydrogen, halogen, hydroxy, —CF₃, and —CN.

Another embodiment of the present invention is a compound of formula 1wherein Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl. Therefore,the invention provides a compound of formula 1 wherein Ar is a moiety offormula 2 and Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl. Alsoprovided is a compound of formula 1 wherein Ar is a moiety of formula 2,Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, and Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl.

The present invention also contemplates a compound of formula 1 whereinRc independently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl. Accordingly, theinvention provides a compound of formula 1 wherein Ar is a moiety offormula 2 and Rc independently represents a substituent selected fromthe group consisting of hydrogen, hydroxy, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, —and (C₂–C₉)heterocyclyl, or two Rc substituents maybe taken together with the atom to which hey are attached to form acyclic group, —(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl. In apreferred embodiment, Ar is a moiety of formula 2, Rc independentlyrepresents a substituent selected from the group consisting of hydrogen,hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —and (C₂–C₉)heterocyclyl, ortwo Rc substituents may be taken together with the atom to which theyare attached to form a cyclic group, —(C₃–C₁₀)-cycloalkyl or—(C₂–C₉)-heterocyclyl, and Ra is selected from the group consisting ofhydrogen, halogen, hydroxy, —CF₃, and —CN.

Moreover, an embodiment of the present invention is a compound offormula 1 wherein Ar is a moiety of formula 2, Rc independentlyrepresents a substituent selected from the group consisting of hydrogen,hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and (C₂–C₉)heterocyclyl, ortwo Rc substituents may be taken together with the atom to which theyare attached to form a cyclic group, —(C₃–C₁₀)-cycloalkyl or—(C₂–C₉)-heterocyclyl, Ra is selected from the group consisting ofhydrogen, halogen, hydroxy, —CF₃, and —CN, and Rb is selected from thegroup consisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and—(C₂–C₉)heterocyclyl.

Still further, another embodiment of the invention is a compound offormula 1 wherein A is a suitably substituted —(C₂–C₉)heterocyclyl groupinclusive of the ring nitrogen atom at the juncture between cyclicmoiety A and the C-4 position of the pyrimidine ring of formula 1;wherein A is optionally substituted by 1 to 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, —NHSO₂R¹,—N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹,SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionallyinterrupted by one to three elements selected from the group consistingof —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR³.

Alternatively, the invention provides a compound of formula 1 wherein Ais a suitably substituted —(C₂–C₇)heterocyclyl group wherein twoadjacent methylene carbons of said —(C₂–C₇)heterocyclyl group are fusedto a phenyl or —(C₂–C₅)heteroaryl group; wherein A is optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, —NHSO₂R¹, —N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹,SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionallyinterrupted by one to three elements selected from the group consistingof —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR³.

Also provided is a compound of formula 1 wherein Ar is a fused ringsystem selected from the group consisting of:

Accordingly, the invention provides a compound of formula 1 wherein Aris a fused ring system selected from the group consisting of:

Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)Cycloalkyl, and —(C₂–C₉)heterocyclyl, and Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl.

Further provided is a compound of formula 1 wherein Ar is a fused ringsystem selected from the group consisting of:

Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, and Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl, and

A is a suitably substituted —(C₂–C₉)heterocyclyl group inclusive of thering nitrogen atom at the juncture between cyclic moiety A and the C-4position of the pyrimidine ring of formula I; wherein A is optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, —NHSO₂R¹, —N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹,SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionallyinterrupted by one to three elements selected from the group consistingof —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR³.

Still further, the invention contemplates a compound of formula 1wherein Ar is a fused ring system selected from the group consisting of:

Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, and Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl; and

A is a suitably substituted —(C₂–C₇)heterocyclyl group wherein twoadjacent methylene carbons of said —(C₂–C₇)heterocyclyl group are fusedto a phenyl or —(C₂–C₅)heteroaryl group; wherein A is optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, —NHSO₂R¹, —N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹,SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionallyinterrupted by one to three elements selected from the group consistingof —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR³.

The following is a non-limiting list of compounds according to thepresent invention:

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-yl}-methanesulfonamide;

5-[4-(4-Methanesulfonyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-ylmethyl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-ylmethyl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(S)-ylmethyl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-yl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(S)-yl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(S)-yl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(R)-yl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(R)-ylmethyl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-ylmethyl}-methanesulfonamide;

N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-yl}-methanesulfonamide;

N-Methyl-N-{4-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-morpholin-2-ylmethyl}-methanesulfonamide;

N-Methyl-N-{1-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-yl}-methanesulfonamide;

N-Methyl-N-{1-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-ylmethyl}-methanesulfonamide;

5-[4-(4-Methanesulfonyl-[1,4]diazepan-1-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;and

5-[4-(1,3-Dihydro-isoindol-2-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In one embodimentthe method comprises comprising administering to a mammal an amount of acompound of formula 1 that is effective in treating said cancer solidtumor. In one preferred embodiment the solid tumor is breast, lung,colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma),endocrine, uterine, testicular, and bladder cancer.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with an anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with another anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens. The invention also contemplates a pharmaceuticalcomposition for treating abnormal cell growth wherein the compositionincludes a compound of formula 1, as defined above, or apharmaceutically acceptable salt, solvate or prodrug thereof, that iseffective in treating abnormal cell growth, and another anti-tumor agentselected from the group consisting of mitotic inhibitors, alkylatingagents, anti-metabolites, intercalating antibiotics, growth factorinhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors,biological response modifiers, antibodies, cytotoxics, anti-hormones,and anti-androgens.

This invention also relates to a method for the treatment of a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula 1,as defined above, or a pharmaceutically acceptable salt, solvate orprodrug thereof, that is effective in treating said disorder incombination with one or more anti-tumor agents listed above. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, Paget's disease, humoral hypercalcemia of malignancy,hypercalcemia from tumors metastatic to bone, and osteoporosis inducedby glucocorticoid treatment; coronary restenosis; and certain microbialinfections including those associated with microbial pathogens selectedfrom adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

This invention also relates to a method of (and to a pharmaceuticalcomposition for) treating abnormal cell growth in a mammal whichcomprise an amount of a compound of formula 1, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, in combination with anamount of one or more substances selected from anti-angiogenesis agents,signal transduction inhibitors, and antiproliferative agents, whichamounts are together effective in treating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of formula 1 in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), andArcoxia (etoricoxib). Examples of useful matrix metalloproteinaseinhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO96/27583 (published Mar. 7, 1996), European Patent Application No.97304971.1 (filed Jul. 8, 1997), European Patent Application No.99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998),WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13,1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (publishedAug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931,788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 331, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. PCT/IB98/01113 (filed Jul. 21, 1998),European Patent Application No. 99302232.1 (filed Mar. 25, 1999), GreatBritain patent application number 9912961.1 (filed Jun. 3, 1999), U.S.Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat.No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issuedJan. 19, 1999), and European Patent Publication 780,386 (published Jun.25, 1997), all of which are herein incorporated by reference in theirentirety. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds of the present invention are AG-3340, RO 32-3555, RS 13-0830,and the compounds recited in the following list:

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionicacid;

3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide;

(2R,3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;

4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionicacid;

4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;

3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide;

(2R,3R)1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionicacid;

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionicacid;

3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide;

3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; and

3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide;

and pharmaceutically acceptable salts, solvates and prodrugs of saidcompounds.

VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 (Sugen Inc.of South San Francisco, Calif., USA), can also be combined with acompound of formula 1. VEGF inhibitors are described in, for example inWO 99/24440 (published May 20, 1999), PCT International ApplicationPCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17,1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504(issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat.No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issuedMar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), U.S.Pat. No. U.S. Pat. No. 6,653,308 (issued Nov. 25, 2003), WO 99/10349(published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO97/22596 (published Jun. 26, 1997), WO 98/54093 (published Dec. 3,1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (publishedApr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of whichare herein incorporated by reference in their entirety. Other examplesof some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland,Wash., USA); Avastin, an anti-VEGF monoclonal antibody of Genentech,Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozymefrom Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), may be administered incombination with a compound of formula 1. Such erbB2 inhibitors includeHerceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include thosedescribed in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), each of which is herein incorporated by reference in itsentirety. ErbB2 receptor inhibitors useful in the present invention arealso described in U.S. Provisional Application No. 60/117,341, filedJan. 27, 1999, and in U.S. Provisional Application No. 60/117,346, filedJan. 27, 1999, both of which are herein incorporated by reference intheir entirety. Other erbb2 receptor inhibitors include TAK-165 (Takeda)and GW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties, and some oftyrosine kinase inhibitors have been identified as erbB2 receptorinhibitors. More recently, five European patent publications, namely EP0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun.22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1(published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30,1992), refer to certain bicyclic derivatives, in particular quinazolinederivatives, as possessing anti-cancer properties that result from theirtyrosine kinase inhibitory properties. Also, World Patent Application WO92/20642 (published Nov. 26, 1992), refers to certain bis-mono andbicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitorsthat are useful in inhibiting abnormal cell proliferation. World PatentApplications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (publishedMar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434(published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO98/02438 (published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose. Other patent applications that refer toanti-cancer compounds are World Patent Application WO00/44728 (publishedAug. 3, 2000), EP 1029853A1 (published Aug. 23, 2000), and WO01/98277(published Dec. 12, 2001) all of which are incorporated herein byreference in their entirety.

Other antiproliferative agents that may be used with the compounds ofthe present invention include inhibitors of the enzyme farnesyl proteintransferase and inhibitors of the receptor tyrosine kinase PDGFr,including the compounds disclosed and claimed in the following U.S.patent application Ser. No. 09/221,946 (filed Dec. 28, 1998); Ser. No.09/454,058 (filed Dec. 2, 1999); Ser. No. 09/501,163 (filed Feb. 9,2000); Ser. No. 09/539,930 (filed Mar. 31, 2000); Ser. No. 09/202,796(filed May 22, 1997); Ser. No. 09/384,339 (filed Aug. 26, 1999); andSer. No. 09/383,755 (filed Aug. 26, 1999); and the compounds disclosedand claimed in the following U.S. provisional patent applications:60/168,207 (filed Nov. 30, 1999); 60/170,119 (filed Dec. 10, 1999);60/177,718 (filed Jan. 21, 2000); 60/168,217 (filed Nov. 30, 1999), and60/200,834 (filed May 1, 2000). Each of the foregoing patentapplications and provisional patent applications is herein incorporatedby reference in their entirety.

A compound of formula 1 may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present invention include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

A compound of formula I may be applied as a sole therapy or may involveone or more other anti-tumor substances, for example those selectedfrom, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, oxaliplatin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil,capecitabine, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred anti-metabolites disclosed in European PatentApplication 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex (tamoxifen) or, for example anti-androgens such as Casodex(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

The compounds of the present invention may be used alone or incombination with one or more of a variety of anti-cancer agents orsupportive care agents. For example, the compounds of the presentinvention may be used with cytotoxic agents, e.g., one or more selectedfrom the group consisting of a camptothecin, irinotecan HCl (Camptosar),edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere),paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate(Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. Theinvention also contemplates the use of the compounds of the presentinvention together with hormonal therapy, e.g., exemestane (Aromasin),Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar,and combinations thereof. Further, the invention provides a compound ofthe present invention alone or in combination with one or moresupportive care products, e.g., a product selected from the groupconsisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin,Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separatedosing of the individual components of the treatment.

The compounds of the invention may be used with antitumor agents,alkylating agents, antimetabolites, antibiotics, plant-derived antitumoragents, camptothecin derivatives, tyrosine kinase inhibitors,antibodies, interferons, and/or biological response modifiers. In thisregard, the following is a non-limiting list of examples of secondaryagents that may be used with the compounds of the invention.

-   Alkylating agents include, but are not limited to, nitrogen mustard    N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,    mitobronitol, carboquone, thiotepa, ranimustine, nimustine,    temozolomide, AMD-473, altretamine, AP-5280, apaziquone,    brostallicin, bendamustine, carmustine, estramustine, fotemustine,    glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol;    platinum-coordinated alkylating compounds include but are not    limited to, cisplatin, carboplatin, eptaplatin, lobaplatin,    nedaplatin, oxaliplatin or satrplatin;-   Antimetabolites include but are not limited to, methotrexate,    6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU)    alone or in combination with leucovorin, tegafur, UFT,    doxifluridine, carmofur, cytarabine, cytarabine ocfosfate,    enocitabine, S-1, gemcitabine, fludarabin, 5-azacitidine,    capecitabine, cladribine, clofarabine, decitabine, eflornithine,    ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan,    nelarabine, nolatrexed, ocfosfate, disodium premetrexed,    pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,    vidarabine, vincristine, vinorelbine; or for example, one of the    preferred anti-metabolites disclosed in European Patent Application    No. 239362 such as    N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic    acid;-   Antibiotics include but are not limited to: aclarubicin, actinomycin    D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin,    elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C,    nemorubicin, neocarzinostatin, peplomycin, pirarubicin,    rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin;-   Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron,    anastrozole (Arimidex), doxercalciferol, fadrozole, formestane,    anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant,    Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara),    or anti-androgens such as bicalutamide, flutamide, mifepristone,    nilutamide, Casodex®    (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)    and combinations thereof;-   Plant derived anti-tumor substances include for example those    selected from mitotic inhibitors, for example vinblastine, docetaxel    (Taxotere) and paclitaxel;-   Cytotoxic topoisomerase inhibiting agents include one or more agents    selected from the group consisting of aclarubicn, amonafide,    belotecan, camptothecin, 10-hydroxycamptothecin,    9-aminocamptothecin, diflomotecan, irinotecan HCl (Camptosar),    edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan,    lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan,    sobuzoxane, SN-38, tafluposide, and topotecan, and combinations    thereof;-   Immunologicals include interferons and numerous other immune    enhancing agents. Interferons include interferon alpha, interferon    alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a    or interferon gamma-n1. Other agents include filgrastim, lentinan,    sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab,    BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin,    ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine    (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin,    tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab,    mitumomab, oregovomab, pemtumomab, Provenge;-   Biological response modifiers are agents that modify defense    mechanisms of living organisms or biological responses, such as    survival, growth, or differentiation of tissue cells to direct them    to have anti-tumor activity. Such agents include krestin, lentinan,    sizofiran, picibanil, or ubenimex;-   Other anticancer agents include alitretinoin, ampligen, atrasentan    bexarotene, bortezomib. Bosentan, calcitriol, exisulind,    finasteride, fotemustine, ibandronic acid, miltefosine,    mitoxantrone, 1-asparaginase, procarbazine, dacarbazine,    hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286,    Velcade, Tarceva, or tretinoin;-   Other anti-angiogenic compounds include acitretin, fenretinide,    thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide,    combretastatin A-4, endostatin, halofuginone, rebimastat, removab,    Revlimid, squalamine, ukrain and Vitaxin;-   Platinum-coordinated compounds include but are not limited to,    cisplatin, carboplatin, nedaplatin, or oxaliplatin;-   Camptothecin derivatives include but are not limited to    camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,    irinotecan, SN-38, edotecarin, and topotecan;-   Tyrosine kinase inhibitors are iressa or SU5416;-   Antibodies include Herceptin, Erbitux, Avastin, or Rituximab;-   Interferons include interferon alpha, interferon alpha-2a,    interferon, alpha-2b, interferon beta, interferon gamma-1a or    interferon gamma-n1;-   Biological response modifiers are agents that modify defense    mechanisms of living organisms or biological responses, such as    survival, growth, or differentiation of tissue cells to direct them    to have anti-tumor activity. Such agents include krestin, lentinan,    sizofiran, picibanil, or ubenimex; and-   Other antitumor agents include mitoxantrone, I-asparaginase,    procarbazine, dacarbazine, hydroxycarbamide, pentostatin, or    tretinoin.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The compounds of the present invention are potent inhibitors of the FAKprotein tyrosine kinases, and thus are all adapted to therapeutic use asantiproliferative agents (e.g., anticancer), antitumor (e.g., effectiveagainst solid tumors), antiangiogenesis (e.g., stop or preventproliferationation of blood vessels) in mammals, particularly in humans.In particular, the compounds of the present invention are useful in theprevention and treatment of a variety of human hyperproliferativedisorders such as malignant and benign tumors of the liver, kidney,bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic,lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, headand neck, and other hyperplastic conditions such as benign hyperplasiaof the skin (e.g., psoriasis) and benign hyperplasia of the prostate(e.g., BPH). It is, in addition, expected that a compound of the presentinvention may possess activity against a range of leukemias and lymphoidmalignancies.

In one preferred embodiment of the present invention cancer is selectedfrom lung cancer, bone cancer, pancreatic cancer, gastric, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, gynecological, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, squamous cell,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain,pituitary adenoma, or a combination of one or more of the foregoingcancers.

In a more preferred embodiment cancer is selected a solid tumor, suchas, but not limited to, breast, lung, colon, brain, prostate, stomach,pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular,and bladder.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

A particular aspect of this invention is directed to methods fortreating or preventing a condition that presents with low bone mass in amammal (including a human being) which comprise administering to amammal in need of such treatment a condition that presents with low bonemass treating amount of a Formula I compound or a pharmaceuticallyacceptable salt of said compound.

This invention is particularly directed to such methods wherein thecondition that presents with low bone mass is osteoporosis, frailty, anosteoporotic fracture, a bone defect, childhood idiopathic bone loss,alveolar bone loss, mandibular bone loss, bone fracture, osteotomy,periodontitis or prosthetic ingrowth.

A particular aspect of this invention is directed to methods fortreating osteoporosis in a mammal (including a human being) whichcomprise administering to a mammal in need of such treatment anosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to methods for treating abone fracture or an osteoporotic fracture in a mammal which compriseadministering to a mammal in need of such treatment a bone fracturetreating or an osteoporotic fracture treating amount of a Formula Icompound or a pharmaceutically acceptable salt of said compound.

The term “osteoporosis” includes primary osteoporosis, such as senile,postmenopausal and juvenile osteoporosis, as well as secondaryosteoporosis, such as osteoporosis due to hyperthyroidism or Cushingsyndrome (due to corticosteroid use), acromegaly, hypogonadism,dysosteogenesis and hypophospatasemia.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 1 mg to 1 gram, preferably 1 mg to 250 mg, morepreferably 10 mg to 100 mg.

The present invention also encompasses sustained release compositions.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula 1 can be prepared using the synthetic routeoutlined in Schemes 1. The substituents in Schemes 1 have the samemeaning as the substituents defined for formula 1.

Compounds of formula 1 can be prepared starting from the arylaminesystem (5), e.g., 4-, 5-, 6-, or 7-amino-oxindole and pyrimidine (6).Combining 6 with a Lewis Acid at temperatures ranging from −15 to 45° C.for a time period of 10–60 minutes in an inert solvent (or solventmixture) followed by addition of 5 and a suitable base provides afterthe period of 1–24 h the intermediate 4-chloropyrimidine (7) in highyields. Examples of inert solvents include but are not limited to THF,1,4-dioxane, n-BuOH, i-PrOH, dichloromethane and 1,2-dichloroethane.Examples of suitable bases employed may include but are not limited to(i) non-nucleophilic organic bases for example triethylamine ordiisopropylethylamine (ii) inorganic bases such as potassium carbonateor cesium carbonate or (iii) resin bound bases such as MP-carbonate.

Examples of Lewis Acids include but are not limited to halide salts ofmagnesium, copper, zinc, tin or titanium. In the next reaction,intermediate 7 is reacted with an amine of the formula 8 either neat orin the presence of an inert solvent (or solvent mixture) at temperaturesranging from 0 to 150° C. to provide the compounds of formula 1.Optionally this reaction can be run in the presence of a suitable base.Examples of suitable solvents for this reaction include but are notlimited to THF, 1,4-dioxane, DMF, N-methyl-pyrrolidinone, EtOH, n-BuOH,i-PrOH, dichloromethane, 1,2-dichloroethane, DMSO or acetonitrile.Suitable bases are as outlined above.

Compounds of the present invention may be synthetically transformed intoother compounds of the invention by techniques known to those skilled inthe art. Simply for illustrative purposes and without limitation, suchmethods include:

a) removal of a protecting group by methods outlined in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Second Edition,John Wiley and Sons, New York, 1991; e.g., emoval of a BOC protectinggroup with an acid source such as HCl or trifluoroacetic acid.

b) displacement of a leaving group (halide, mesylate, tosylate, etc)with functional groups such as but not limited to a primary or secondaryamine, thiol or alcohol to form a secondary or tertiary amine, thioetheror ether, respectively.

c) treatment of phenyl (or substituted phenyl) carbamates with primaryof secondary amines to form the corresponding ureas as in Thavonekham, Bet. al. Synthesis (1997), 10, p 1189;

d) reduction of propargyl or homopropargyl alcohols or N—BOC protectedprimary amines to the corresponding E-allylic or E-homoallylicderivatives by treatment with sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) as in Denmark, S. E.; Jones, T. K. J. Org. Chem. (1982)47, 4595–4597 or van Benthem, R. A. T. M.; Michels, J. J.; Speckamp, W.N. Synlett (1994), 368–370;

e) reduction of alkynes to the corresponding Z-alkene derivatives bytreatment hydrogen gas and a Pd catalyst as in Tomassy, B. et. al.Synth. Commun. (1998), 28, p 1201;

f) treatment of primary and secondary amines with an isocyanate, acidchloride (or other activated carboxylic acid derivative), alkyl/arylchloroformate or sulfonyl chloride to provide the corresponding urea,amide, carbamate or sulfonamide;

g) reductive amination of a primary or secondary amine using an aldehydeor ketone and an appropriate reducing reagent;

h) treatment of alcohols with an isocyanate, acid chloride (or otheractivated carboxylic acid derivative), alkyl/aryl chloroformate orsulfonyl chloride to provide the corresponding carbamate, ester,carbonate or sulfonic acid ester.

Amines of the formula 8 may be purchased and used directly oralternatively be prepared by one skilled in the art using ordinarychemical transformations.

The in vitro activity of the compounds of formula 1 may be determined bythe following procedure. More particularly, the following assay providesa method to determine whether compounds of the formula 1 inhibit thetyrosine kinase activity of the catalytic construct FAK(410-689). Theassay is an ELISA-based format, measuring the inhibition of poly-glu-tyrphosphorylation by FAK(410-689).

The assay protocol has three parts:

I. Purification and cleavage of His-FAK(410-689)

II. FAK410-689 (a.k.a. FAKcd) Activation

III. FAKcd Kinase ELISA

Materials:

-   -   Ni-NTA agarose (Qiagen)    -   XK-16 column (Amersham-Pharmacia)    -   300 mM Imidizole    -   Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.)    -   Antibody: Anti-Phosphotyrosine HRP-Conjugated Py20 (Transduction        labs)    -   FAKcd: Purified and activated in house    -   TMB Microwell Peroxidase Substrate (Oncogene Research Products        #CL07)    -   BSA: Sigma #A3294    -   Tween-20: Sigma #P1379    -   DMSO: Sigma #D-5879    -   D-PBS: Gibco #14190-037.        Reagents for Purification:    -   Buffer A: 50 mM HEPES pH 7.0

500 mM NaCl

0.1 mM TCEP

Complete™ protease inhibitor cocktail tablets (Roche)

-   -   Buffer B: 25 mM HEPES pH 7.0

400 mM NaCl

0.1 mM TCEP

-   -   Buffer C: 10 mM HEPES pH 7.5

200 mM Ammonium Sulfate

0.1 mM TCEP.

Reagents for Activation

-   -   FAK(410-689): 3 tubes of frozen aliquots at 150 ul/tube for a        total of 450 ul at 1.48 mg/ml (660 ug)    -   His-Src(249-524): ˜0.74 mg/ml stock in 10 mM HEPES, 200 mM        (NH4)2SO4    -   Src reaction buffer (Upstate Biotech):        -   100 mM Tris-HCl pH7.2        -   125 mM MgCl2        -   25 mM MnCl2        -   2 mM EDTA        -   250 uM Na3VO4        -   2 mM DTT    -   Mn2+/ATP cocktail (Upstate Biotech)        -   75 mM MnCl2        -   500 uM ATP        -   20 mM MOPS pH 7.2        -   1 mM Na3VO4        -   25 mM glycerol phosphate        -   5 mM EGTA        -   1 mM DTT    -   ATP: 150 mM stock    -   MgCl₂: 1 M Stock    -   DTT: 1 M stock        Reagents for FAKcd Kinase ELISA    -   Phosphorylation Buffer:        -   50 mM HEPES, pH 7.5        -   125 mM NaCl        -   48 mM MgCl2    -   Wash Buffer: TBS+0.1% Tween-20.    -   Blocking Buffer:        -   Tris Buffer Saline        -   3% BSA        -   0.05% Tween-20, filtered    -   Plate Coating Buffer:        -   50 mg/ml Poly-Glu-Tyr (Sigma #P0275) in Phosphate buffer            Saline (DPBS).    -   ATP: 0.1 M ATP in H2O or HEPES, pH7.        -   Note: ATP Assay Buffer:        -   Make up as 75 uM ATP in PBS, so that 80 ul in        -   120 ul reaction volume=50 uM final ATP concentration.            I. Purification of His-FAKcd(410-689)

1. Resuspend 130 g baculovirus cell paste containing the over expressedHis-FAKcd410-689 recombinant protein in 3 volumes (400 ml) of Buffer A.

2. Lyse cells with one pass on a microfluidizer.

3. Remove cell debris by centrifugation at 4° C. for 35 minutes at14,000 rpm in a Sorval SLA-1500 rotor.

4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTAagarose (Qiagen).

5. Incubate the suspension with gentle rocking at 4° C. for 1 hour.

6. Centrifuge suspension at 700×g in a swinging bucket rotor.

7. Discard the supernatant and resuspend the agarose beads in 20.0 ml ofBuffer A.

8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connectedto a FPLCTM.

9. Wash the agarose-beads with 5 column volumes of Buffer A and eluteoff the column with a step gradient of Buffer A containing 300 mMImidizole.

10. Perform a buffer exchange of the eluted fractions into Buffer B

11. Following buffer exchange, pool the fractions and add thrombin at a1:300 (w/w) ratio and incubated overnight at 13° C. to remove theN-terminal His-tag (His-FAK410-698→FAK410-689 (a.k.a. FAKcd)).

12. Add the reaction mixture back onto the Ni-NTA column equilibratedwith Buffer A and collect the flow-through.

13. Concentrate the flow-through down to 1.7 ml and load directly onto aSuperdex 200 HiLoad 16/60 prep grade column equilibrated with Buffer C.The desired protein elutes between 85–95 ml.

14. Aliquot the FAKcd protein and store frozen at −80° C.

II. FAK Activation

1. To 450 ul of FAK(410-689) at 1.48 mg/ml (660 ug) add the following:

-   -   30 ul of 0.037 mg/ml (1 uM) His-Src(249-524)    -   30 ul of 7.5 mM ATP    -   12 ul of 20 mM MgCl2    -   10 ul Mn2+/ATP cocktail (UpState Biotech.)    -   4 ul of 6.7 mM DTT    -   60 ul Src Reaction Buffer (UpState Biotech.)

2. Incubate Reaction for at least 3 hours at room temperature

At time t₀, almost all of the FAK(410-689) is singly phosphorylated. Thesecond phosphorylation is slow. At t₁₂₀ (t=120 minutes), add 10 ul of150 mM ATP.

T₀=(Start) 90% singly phosphorylated FAK(410-689) (1 PO4)

T₄₃=(43 min) 65% singly phosphorylated (1 PO4), 35% doublyphosphorylated (2 PO4)

T₉₀=(90 min) 45% 1 PO4, 55% 2 PO4

T₁₅₀=15% 1 PO4, 85% 2 PO4

T₂₁₀=<10% 1 PO4, >90% 2 PO4 desalted sample

3. Add 180 ul aliquots of the desalted material to NiNTA spin column andincubate on spin column

4. Spin at 10 k rpm (microfuge), for 5 minutes to isolate and collectflow through (Activated FAK(410-689)) and remove His-Src (captured oncolumn)

III. FAKcd Kinase ELISA

1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10ug/well: Prepare 10 ug/ml of pGT in PBS and aliquot 100 ul/well.Incubate the plates at 37° C. overnight, aspirate the supernatant, washthe plates 3 times with Wash Buffer, and flick to dry before storing at4° C.

2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The stocksare subsequently diluted to 60× of the final concentration in 100% DMSO,and diluted 1:5 in Kinase Phosphorylation Buffer.

3. Prepare a 75 uM working ATP solution in Kinase phosphorylationbuffer. Add 80 ul to each well for a final ATP concentration of 50 uM.

4. Transfer 10 ul of the diluted compounds (0.5 log serial dilutions) toeach well of the pGT assay plate, running each compound in triplicateson the same plate.

5. Dilute on ice, FAKcd protein to 1:1000 in Kinase PhosphorylationBuffer. Dispense 30 ul per well.

6. Note: Linearity and the appropriate dilution must be pre-determinedfor each batch of protein. The enzyme concentration selected should besuch that quantitation of the assay signal will be approximately 0.8–1.0at OD450, and in the linear range of the reaction rate.

7. Prepare both a No ATP control (noise) and a No Compound Control(Signal).

8. (Noise) One blank row of wells receives 10 ul of 1:5 dilutedcompounds in DMSO, 80 ul of Phosphorylation buffer (minus ATP), and 30ul FAKcd solution.

9. (Siganl) Control wells receive 10 ul of 1:5 diluted DMSO (minusCompound) in Kinase phosphorylation buffer, 80 ul of 75 uM ATP, and 30ul of 1:1000 FAKcd enzyme.

10. Incubate reaction at room temperature for 15 minutes with gentleshaking on a plate shaker.

11. Terminate the reaction by aspirating off the reaction mixture andwashing 3 times with wash buffer.

12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to 0.250ug/ml (1:1000 of Stock) in blocking buffer. Dispense 100 ul per well,and incubate with shaking for 30 minutes at R.T.

13. Aspirate the supernatant and wash the plate 3 times with washbuffer.

14. Add 100 ul per well of room temperature TMB solution to initiatecolor development. Color development is terminated after approximately15–30 sec. by the addition of 100 ul of 0.09M H2SO4 per well.

15. The signal is quantitated by measurement of absorbance at 450 nm onthe BioRad microplate reader or a microplate reader capable of readingat OD450.

16. Inhibition of tyrosine kinase activity would result in a reducedabsorbance signal. The signal is typically 0.8–1.0 OD units. The valuesare reported as IC_(50s), uM concentration.

FAK Inducible Cell-based ELISA: Final Protocol

Materials:

Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product#15135ZZ@115.00 USD)

FAKpY397 rabbit polyclonal antibody (Biosource #44624 @315.00 USD)

ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003@60/25 mg USD)

UBI αFAK clone 2A7 mouse monoclonal antibody (Upstate#05-182 @ 289.00USD)

Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs#115-035-146 @95/1.5 ml USD)

SuperBlock TBS (Pierce Product#37535ZZ @99 USD)

Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD)

TMB Peroxidase substrate (Oncogene Research Products #CL07-100 ml @40.00USD)

Na3VO4 Sodium Orthovanadate (Sigma #S6508 @43.95/50 g USD)

MTT substrate (Sigma # M-2128 @25.95/500 mg USD)

Growth Media: DMEM+10% FBS, P/S, Glu, 750 ug/ml Zeocin and 50 ug/mlHygromycin (Zeocin InVitrogen #R250-05 @ 725 USD and HygromyconInVitrogen #R220-05 @ 150 USD)

Mifepristone InVitrogen # H10-01 @ 125 USD

Complete™ EDTA-free Protease Inhibitor pellet Boehringer Mannheim#1873580

FAK cell-based Protocol for selectivity of kinase-dependentphosphoFAKY397

Procedure:

An inducible FAK cell-based assay in ELISA format for the screening ofchemical matter to identify tyrosine kinase specific inhibitors wasdeveloped. The cell-based assay exploits the mechanism of theGeneSwitch™ system (InVitrogen) to exogenously control the expressionand phosphorylation of FAK and the kinase-dependent autophosphorylationsite at residue Y397.

Inhibition of the kinase-dependent autophosphorylation at Y397 resultsin a reduced absorbance signal at OD450. The signal is typically 0.9 to1.5 OD450 units with the noise falling in the range of 0.08 to 0.1 OD450units. The values are reported as IC50s, uM concentration.

On day 1, grow A431•FAKwt in T175 flasks. On the day prior to runningthe FAK cell-assay, seed A431•FAKwt cells in growth media on 96-wellU-bottom plates. Allow cells to sit at 37° C., 5% CO2 for 6 to 8 hoursprior to FAK induction. Prepare Mifepristone stock solution of 10 uM in100% Ethanol. The stock solution is subsequently diluted to 10× of thefinal concentration in Growth Media. Transfer 10 ul of this dilution(final concentration of 0.1 nM Mifepristone) into each well. Allow cellsto sit at 37° C., 5% CO₂ overnight (12 to 16 hours). Also, preparecontrol wells without Mifepristone induction of FAK expression andphosphorylation.

On day 2, coat Goat Anti-Rabbit plate(s) with 3.5 ug/ml ofphosphospecific FAKpY397 polyclonal antibody prepared in SuperBlock TBSbuffer, and allow plate(s) to shake on a plate shaker at roomtemperature for 2 hours. Optionally, control wells may be coated with3.5 ug/ml of control Capture antibody (Whole Rabbit IgG molecules)prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 timesusing buffer. Block Anti-FAKpY397 coated plate(s) with 200 ul per wellof 3% BSA/0.5% Tween Blocking buffer for 1 hour at room temperature onthe plate shaker. While the plate(s) are blocking, prepare compoundstock solutions of 5 mM in 100% DMSO. The stock solutions aresubsequently serially diluted to 100× of the final concentration in 100%DMSO. Make a 1:10 dilution using the 100× solution into growth media andtransfer 10 ul of the appropriate compound dilutions to each wellcontaining either the FAK induced or uninduced control A431 cells for 30minutes at 37° C., 5% CO₂. Prepare RIPA lysis buffer (50 mM Tris-HCl,pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mMNa3VO4, 1 mM NaF, and one Complete™ EDTA-free protease inhibitor pelletper 50 ml solution). At the end of 30 minutes compound treatment, washoff compound 3 times using TBS-T wash buffer. Lyse cells with 100ul/well of RIPA buffer.

To the coated plate, remove blocking buffer and wash 3 times using TBS-Twash buffer. Using a 96-well automated microdispenser, transfer 100 ulof whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKpY397coated plate(s) to capture phosphoFAKY397 proteins. Shake at roomtemperature for 2 hours. Wash off unbound proteins 3 times using TBS-Twash buffer. Prepare 0.5 ug/ml (1:2000 dilution) of UBI αFAK detectionantibody in 3% BSA/0.5% Tween blocking buffer. Dispense 100 ul of UBIαFAK solution per well and shake for 30 minutes at room temperature.Wash off excess UBI αFAK antibody 3 times using TBS-T wash buffer.Prepare 0.08 ug/ml (1:5000 dilution) of secondary Anti-Mouse Peroxidase(Anti-2MHRP) conjugated antibody. Dispense 100 ul per well of theAnti-2MHRP solution and shake for 30 minutes at room temperature. Washoff excess Anti-2MHRP antibody 3 times using TBS-T wash buffer. Add 100ul per well of room temperature TMB substrate solution to allow forcolor development. Terminate the TMB reaction with 100 ul per well ofTMB stop solution (0.09M H2SO4) and quantitate the signal by measurementof absorbance at 450 nm on the BioRad microplate reader.

Additional FAK cell assays are hereby incorporated by reference fromPfizer Ser. No. 60/412,078 entitled “INDUCIBLE FOCAL ADHESION KINASECELL ASSAY”.

In a preferred embodiment, the compounds of the present invention havean in vitro activity as determined by a kinase assay, e.g., such as thatdescribed herein, of less than 500 nM. Preferably, the compounds have anIC₅₀ of less than 25 nM in the kinase assay, and more preferably lessthan 10 nM. In a further preferred embodiment, the compounds exhibit anIC₅₀ in a FAK cell based assay, e.g., such as that described herein, ofless than 1 μM, more preferably less than 100 nM, and most preferablyless than 25 n M.

Still further, the following assay(s) may be used to assess the abilityof a compound of the present invention to inhibit osteoporosis and/orlow bone mass, as described above.

(1) Effect of Test Compound on Body Weight, Body Composition and BoneDensity in the Aged Intact and Ovariectomized Female Rat

This assay may be used to test the effects of a test compound in agedintact or ovariectomized (OVX) female rat model.

Study Protocol

Sprague-Dawley female rats are sham-operated or OVX at 18 months of age,while a group of rats is necropsied at day 0 to serve as baselinecontrols. One day post-surgery, the rats are treated with either vehicleor test compound. The vehicle or test compound is administered twice aweek (Tuesday and Friday) by subcutaneous injection (s.c.), with thetest compound being administered at an average dose of 10 milligrams perkilogram of body weight per day (10 mg/kg/day).

All rats are given s.c. injection of 10 mg/kg of calcein (Sigma, St.Louis, Mo.) for fluorescent bone label 2 and 12 days before necropsy. Onthe day of necropsy, all rats under ketamine/xylazine anesthesia areweighed and undergoe dual-energy X-ray absorptiometry (DXA, QDR-45001W,Hologic Inc., Waltham, Mass.) equipped with Rat Whole Body Scan softwarefor lean and fat body mass determination. The rats are necropsied, thenautopsied and blood is obtained by cardiac puncture. The distal femoralmetaphysis and femoral shafts from each rat are analyzed by peripheralquantitative computerized tomography (pQCT), and volumetric total,trabecular and cortical bone mineral content and density are determined.

Peripheral Quantitative Computerized Tomography (pQCT) Analysis: Excisedfemurs are scanned by a pQCT X-ray machine (Stratec XCT Research M,Norland Medical Systems, Fort Atkinson, Wis.) with software version5.40. A 1 millimeter (mm) thick cross section of the femur metaphysis istaken at 5.0 mm (proximal femoral metaphysis, a primary cancellous bonesite) and 13 mm (femoral shafts, a cortical bone site) proximal from thedistal end with a voxel size of 0.10 mm. Cortical bone is defined andanalyzed using contour mode 2 and cortical mode 4. An outer thresholdsetting of 340 mg/cm³ is used to distinguish the cortical shell fromsoft tissue and an inner threshold of 529 mg/cm³ to distinguish corticalbone along the endocortical surface. Trabecular bone is determined usingpeel mode 4 with a threshold of 655 mg/cm³ to distinguish (sub)corticalfrom cancellous bone. An additional concentric peel of 1% of the definedcancellous bone is used to ensure that (sub)cortical bone is eliminatedfrom the analysis. Volumetric content, density, and area are determinedfor both trabecular and cortical bone (Jamsa T. et al., Bone 23:155–161,1998; Ke, H. Z. et al., Journal of Bone and Mineral Research,16:765–773, 2001).

Vaginal histology: Vaginal tissue is fixed and embedded in paraffin.Five micron sections are cut and stained with Alcian Blue staining.Histology examination of vaginal luminal epithelial thickness andmucopolysaccharide (secreted cells) is performed.

The experimental groups for the protocol are as follows:

Group I: Baseline controls

Group II: Sham+Vehicle

Group III: OVX+Vehicle

Group IV: OVX+Test Compound at 10 mg/kg/day (in Vehicle)

(2) Fracture Healing Assays

(a) Assay for Effects on Fracture Healing After Systemic Administration

Fracture Technique: Sprage-Dawley rats at 3 months of age areanesthetized with Ketamine. A 1 cm incision is made on the anteromedialaspect of the proximal part of the right tibia or femur. The followingdescribes the tibial surgical technique. The incision is carried throughto the bone, and a 1 mm hole is drilled 4 mm proximal to the distalaspect of the tibial tuberosity 2 mm medial to the anterior ridge.Intramedullary nailing is performed with a 0.8 mm stainless steel tube(maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the sameconditions as the bones). No reaming of the medullary canal isperformed. A standardized closed fracture is produced 2 mm above thetibiofibular junction by three-point bending using specially designedadjustable forceps with blunt jaws. To minimize soft tissue damage, careis taken not to displace the fracture. The skin is closed withmonofilament nylon sutures. The operation is performed under sterileconditions. Radiographs of all fractures are taken immediately afternailing, and rats with fractures outside the specified diaphyseal areaor with displaced nails are excluded. The remaining animals are dividedrandomly into the following groups with 10–12 animals per each subgroupper time point for testing the fracture healing. The first groupreceives daily gavage of vehicle (water:100% Ethanol=95:5) at 1 ml/rat,while the others receive daily gavage from 0.01 to 100 mg/kg/day of thecompound to be tested (1 ml/rat) for 10, 20,40 and 80 days.

At 10, 20, 40 and 80 days, 10–12 rats from each group are anesthetizedwith Ketamine and sacrificed by exsanguination. Both tibiofibular bonesare removed by dissection and all soft tissue is stripped. Bones from5–6 rats for each group are stored in 70% ethanol for histologicalanalysis, and bones from another 5–6 rats for each group are stored in abuffered Ringer's solution (+4° C., pH 7.4) for radiographs andbiomechanical testing which is performed.

Histological Analysis: The methods for histologic analysis of fracturedbone have been previously published by Mosekilde and Bak (The Effects ofGrowth Hormone on Fracture Healing in Rats: A Histological Description.Bone, 14:19–27, 1993). Briefly, the fracture site is sawed 8 mm to eachside of the fracture line, embedded undecalcified in methymethacrylate,and cut frontals sections on a Reichert-Jung Polycut microtome in 8 μmthick. Masson-Trichrome stained mid-frontal sections (including bothtibia and fibula) are used for visualization of the cellullar and tissueresponse to fracture healing with and without treatment. Sirius redstained sections are used to demonstrate the characteristics of thecallus structure and to differentiate between woven bone and lamellarbone at the fracture site. The following measurements are performed: (1)fracture gap—measured as the shortest distance between the cortical boneends in the fracture, (2) callus length and callus diameter, (3) totalbone volume area of callus, (4) bony tissue per tissue area inside thecallus area, (5) fibrous tissue in the callus, and (6) cartilage area inthe callus.

Biomechanical Analysis: The methods for biomechanical analysis have beenpreviously published by Bak and Andreassen (The Effects of Aging onFracture Healing in Rats. Calcif Tissue Int 45:292–297, 1989). Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedure. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

(a) Assay for Effects on Fracture Healing After Local Administration

Fracture Technique: Female or male beagle dogs at approximately 2 yearsof age are used under anesthesia in the study. Transverse radialfractures are produced by slow continuous loading in three-point bendingas described by Lenehan et al. (Lenehan, T. M.; Balligand, M.;Nunamaker, D. M.; Wood, F. E.: Effects of EHDP on Fracture Healing inDogs. J Orthop Res 3:499–507; 1985). A wire is pulled through thefracture site to ensure complete anatomical disruption of the bone.Thereafter, local delivery of prostaglandin agonists to the fracturesite is achieved by slow release of compound delivered by slow releasepellets or by administration of the compounds in a suitable formulationsuch as a paste gel solution or suspension for 10, 15, or 20 weeks.

Histological Analysis: The methods for histologic analysis of fracturedbone have been previously published by Peter et al. (Peter, C. P.; Cook,W. O.; Nunamaker, D. M.; Provost, M. T.; Seedor, J. G.; Rodan, G. A.Effects of alendronate on fracture healing and bone remodeling in dogs.J. Orthop. Res. 14:74–70, 1996) and Mosekilde and Bak (The Effects ofGrowth Hormone on Fracture Healing in Rats: A Histological Description.Bone, 14:19–27, 1993). Briefly, after sacrifice, the fracture site issawed 3 cm to each side of the fracture line, embedded undecalcified inmethymethacrylate, and cut on a Reichert-Jung Polycut microtome in 8 μmthick of frontal sections. Masson-Trichrome stained mid-frontal sections(including both tibia and fibula) are used for visualization of thecellullar and tissue response to fracture healing with and withouttreatment. Sirius red stained sections are used to demonstrate thecharacteristics of the callus structure and to differentiate betweenwoven bone and lamellar bone at the fracture site. The followingmeasurements are performed: (1) fracture gap—measured as the shortestdistance between the cortical bone ends in the fracture, (2) calluslength and callus diameter, (3) total bone volume area of callus, (4)bony tissue per tissue area inside the callus area, (5) fibrous tissuein the callus, (6) cartilage area in the callus.

Biomechanical Analysis: The methods for biomechanical analysis have beenpreviously published by Bak and Andreassen (The Effects of Aging onFracture Healing in Rats. Calcif Tissue Int 45:292–297, 1989) and Peteret al. (Peter, C. P.; Cook, W. O.; Nunamaker, D. M.; Provost, M. T.;Seedor, J. G.; Rodan, G. A. Effects of Alendronate On Fracture HealingAnd Bone Remodeling In Dogs. J. Orthop. Res. 14:74–70, 1996). Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedures. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other substances, such as those listed hereinabove, includingfor example, vinblastine; alkylating agents, for example cis-platin,carboplatin and cyclophosphamide; anti-metabolites, for example5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example,one of the preferred anti-metabolites disclosed in European PatentApplication No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex (tamoxifen) or, for example anti-androgens such as Casodex(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX™ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 mL/minute.

EXAMPLES

General Methods:

Preparation of 5-nitro-oxindole

To a solution of oxindole (26 g) in 100 mL of concentrated sulfuric acidat −15° C. was added fuming nitric acid (8.4 mL) dropwise. Carefulattention was paid to maintain the reaction temperature at −15° C. Afterthe addition was complete, the reaction was stirred for 30 minutes andthen poured into ice water. A yellow precipitate was formed which wasisolated by filtration to provide 34 grams (98%) of 5-nitro oxindole.

Preparation of 5-amino-oxindole

To a solution of 5-nitro-oxindole (25 g) in 120 mL of dimethylacetamidein a Parr bottle was added 10% Pd/C (0.5 g). The mixture washydrogenated (40 psi H2) for 16 hours. The catalyst was removed byfiltration and the filtrate was diluted with ether (2 L) to provide5-amino-oxindole (10.5 g; 50%).

Preparation of 2,4-dichloro-5-trifluoromethylpyrimidine (6)

5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride(655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equippedwith overhead stirrer, a reflux condenser, an addition funnel and aninternal theromocouple. The contents were maintained under a nitrogenatmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv)was added in one portion to the slurry, resulting in a moderateexotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was thenadded dropwise over 15 minutes at such a rate that the internaltemperature of the reaction reached 85–90° C. by the end of theaddition. By the end of the amine addition the reaction mixture was ahomogenous light-orange solution. Heating was initiated and the orangesolution was maintained at 100° C. for 20 hours, at which time HPLCanalysis of the reaction mixture indicated that the starting materialwas consumed. External heating was removed and the contents of the flaskwere cooled to 40° C. and then added dropwise to a cooled mixture of 3NHCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature ofthe quench pot between 10 and 15° C. The layers were separated, and theaqueous layer was extracted once with ether (1 L). The combined organiclayers were combined, washed with water until the washes were neutral(5×1.5 L washes), dried with MgSO₄ and concentrated to provide 288 g(95% yield) of a light yellow-orange oil of 96% purity (HPLC). Thismaterial can be further purified by distillation (bp 109° C. at 79mmHg).

Preparation of5-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one:

To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (214.8 g;0.921 mol) in 1:1 DCE/tBuOH (1.240 L) was added Zinc chloride 1 Msolution in ether (1 eq; 0.921 L). After 0.5 hour, 5-amino-oxindole (124g; 0.837 mol) was added followed by triethylamine (129.4 ml; 0.921 mol)keeping temperature at 25° C. The reaction was allowed to stir at roomtemperature overnight, then was concentrated and the product trituratedfrom methanol as a yellow solid (224.3 g; 82%). ¹H NMR (DMSO-d₆, 400MHz) δ 3.29 (s, 2H), 6.76 (d, J=7.9 Hz, 2H), 7.39 (d, J=8.3 Hz), 7.51(br s, 1H), 8.71 (s, 1H), 10.33 (s, 1H), 10.49 (s, 1H). ¹³C NMR(DMSO-d₆, 100 MHz) δ 177.0, 161.3, 158.7 (br), 140.7, 132.8, 126.9,123.7 (q, J=268 Hz), 121.0, 118.7, 111.2 (q, J=32 Hz), 109.6, 36.7; HPLCret. time: 5.759 min. LRMS (M+) 329.1, 331.1.

Example 1 Preparation of5-[4-(4-Methanesulfonyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one

5-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one(100 mg; 0.30 mmol) was added to 0.8 mL of anhydrous DMF followed by1-(methylsulfonyl)piperazine monotrifluoroacetic acid salt (84 mg; 0.30mmol) and triethylamine (0.127 mL, 0.90 mmol).

The reaction was heated to 100° C. for one hour. After cooling to roomtemperature, DMF(1 mL) was added and the reaction was purified byreverse phase preparative HPLC (30×50 mm XTerra C18 prep column) elutingat 40 mL/min with a gradient solvent method of 1:4 acetonitrile:0.1%NH4OH to 4:1 acetonitrile/0.1% NH₄OH over 10 minutes. The desiredproduct eluted with a retention time of 5.12 minutes which wasconcentrated to provide 46 mg (33% yield). ¹H NMR (DMSO-d6, 400 MHz) □2.88 (s, 3H), 3.20 (m, 4H), 3.45 (s, 2H), 3.58 (m, 4H), 6.72 (d, J=8 Hz;1H) 7.37 (m, 2H), 7.50 (s, 1H), 8.37 (s, 1H), 9.68 (br s, 1H), 10.2 (s,1H); HPLC ret. time: 5.323 (97% purity) LRMS (MH+) 457.4.

The following compounds of the invention were prepared by heatingchloropyrimidine with an appropriate amine as in Example 1. Amines usedin these reactions were either obtained commercially and used asreceived or alternatively they were prepared by common synthetic methodsfor amines known to those skilled in the art. Unless otherwise noted,compounds having chiral centers were prepared as racemic mixtures.

TABLE 1 HPLC Retention LRMS Name Time (min) (MH+)N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.13 471.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-yl}-methanesulfonamide5-[4-(4-Methanesulfonyl-piperazin-1-yl)-5- 5.32 457.4trifluoromethyl-pyrimidin-2-ylamino]-1,3- dihydro-indol-2-oneN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.84 457.4ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-ylmethyl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.05 471.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-ylmethyl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.06 471.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(S)-ylmethyl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.9 457.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-yl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.91 457.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(S)-yl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.16 471.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(S)-yl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.16 471.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(R)-yl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.41 485.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(R)-ylmethyl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.39 485.3ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-ylmethyl}-methanesulfonamideN-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.82 443.2ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-yl}-methanesulfonamideN-Methyl-N-{4-[2-(2-oxo-2,3-dihydro-1H-indol- 5.38 501.25-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-morpholin-2-ylmethyl}-methanesulfonamideN-Methyl-N-{1-[2-(2-oxo-2,3-dihydro-1H-indol- 5.4 471.25-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-yl}-methanesulfonamideN-Methyl-N-{1-[2-(2-oxo-2,3-dihydro-1H-indol- 5.29 471.35-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-ylmethyl}-methanesulfonamide5-[4-(4-Methanesulfonyl-[1,4]diazepan-1-yl)-5- 5.28 471.2trifluoromethyl-pyrimidin-2-ylamino]-1,3- dihydro-indol-2-one5-[4-(1,3-Dihydro-isoindol-2-yl)-5- 7.02 412.2trifluoromethyl-pyrimidin-2-ylamino]-1,3- dihydro-indol-2-one

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated herein by referencein their entireties.

1. A compound of the formula 1

or a pharmaceutically acceptable salt thereof, wherein Ar is selectedfrom:

and ring B is

wherein m is an integer from 0 to 2; Ra represents substituentsindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CF₃, —CN, —NR¹R², —OR¹, —R¹, —CO₂R¹ and —CONR¹R²; Rbrepresents a substituent selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R¹,—CONR¹R²; each Rc independently represents a substituent selected fromthe group consisting of hydrogen, halogen, hydroxy, —CF₃, —CN,—(C₁–C₆)alkyl, —NR¹R², —OR¹, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl,—CO₂R¹, and —CONR¹R² or two Rc substituents may be taken together withthe atom(s) to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl; A is a suitablysubstituted cyclic moiety selected from the group consisting of(a) a—(C₂–C₉)heterocyclyl group inclusive of the ring nitrogen atom at thejuncture between cyclic moiety A and the C-4 position of the pyrimidinering of formula I; and (b) a —(C₂–C₇)heterocyclyl group wherein twoadjacent methylene carbons of said —(C₂–C₇)heterocyclyl group are fusedto a phenyl or —(C₂–C₅)heteroaryl group; wherein A is optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, cyano, R¹, —NR¹R², —NH(CO)R¹,—NR²(CO)R¹, —(C₁–C₆)alkyl-NR¹R², —(C₁–C₆)alkyl-NH(CO)R¹,—(C₁–C₆)alkyl-NR²(CO)R¹ —NHSO₂R¹, —N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —OR¹, —(C₁–C₆)alkyl-OR¹,—(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²;and said cyclic group A is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and NR³; R¹ and R² are each substituents independentlyselected from the group consisting of hydrogen, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and—(C₁–C₉)heteroaryl; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, and —(C₁–C₉)heteroaryl R¹ or R²substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,—CF₃, —CN, —(C₁–C₆)alkyl, —NH(C₁–C₆)alkyl, —NH(C₃–C₇)cycloalkyl,—NH(C₂–C₉)heterocyclyl, —NH(C₆–C₁₀)aryl, —NH(C₁–C₉)heteroaryl,—N((C₁–C₆)alkyl)₂, —N((C₃–C₇)cycloalkyl)₂, —N((C₂–C₉)heterocyclyl)₂,—N((C₆–C₁₀)aryl)₂, —N((C₁–C₉)heteroaryl)₂, —O(C₁–C₆)alkyl,—O(C₃–C₇)cycloalkyl, —O(C₂–C₉)heterocyclyl, —O(C₆–C₁₀)aryl,—O(C₁–C₉)heteroaryl, —(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, or R¹ andR² (2 may be taken together with the atom(s) to which they are attachedto form a —(C₃–C₁₀)cycloalkyl or —(C₂–C₉)heterocyclyl, wherein said—(C₃–C₁₀)cycloalkyl or —(C₂–C₉)heterocyclyl is optionally substituted byone to three moieties selected from the group consisting of hydrogen,halogen, and hydroxy, and said cyclic group is optionally interrupted byone to three elements selected from the group consisting of —(C═O),—SO₂, —S—, —O—, —N—, —NH— and —NR³; R³ is a substituent selected fromthe group consisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, —(C₁–C₉)heteroaryl, —COR¹, and—SO₂R¹; wherein said —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl,—(C₂–C₉)heterocyclyl, —(C₆–C₁₀)aryl, —(C₁–C₉)heteroaryl, —COR¹, and—SO₂R¹R³ radicals are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁–C₆)alkyl, —NH₂, —NHR⁴, —NR⁴ ₂, —OR⁴,—(C₃–C₇)cycloalkyl, —(C₂–C₉)heterocyclyl, —CO₂R⁵, —CONH₂, —CONHR⁵, and—CONR⁵R⁶; wherein R⁵ and R⁶ of —CONR⁵R⁶ may be taken together with theatoms to which they are attached to form a —(C₂–C₉)heterocyclyl; R⁴ andR⁵ are each —(C₁–C₆)alkyl; and R⁶ is hydrogen or —(C₁–C₆)alkyl.
 2. Acompound according to claim 1 wherein A is a suitably substituted—(C₂–C₉)heterocyclyl group inclusive of the ring nitrogen atom at thejuncture between cyclic moiety A and the C-4 position of the pyrimidinering of formula I; wherein A is optionally substituted by 1 to 3substituents independently selected from the group consisting ofhalogen, hydroxyl, cyano, R¹, —NR¹R², —NH(CO)R¹, —NR²(CO)R¹,—(C₁–C₆)alkyl-NR¹R², —(C₁–C₆)alkyl-NH(CO)R¹, —(C₁–C₆)alkyl-NR²(CO)R¹—NHSO₂R¹, —N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹),—(C₁–C₆)alkyl(NHSO₂)(R¹), —(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —OR¹,—(C₁–C₆)alkyl-OR¹, —(C₁–C₆)alkyl—OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂,SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionally interruptedby one to three elements selected from the group consisting of —(C═O),—SO₂, —S—, —O—, —N—, —NH— and —NR³.
 3. A compound according to claim 1wherein A is a suitably substituted —(C₂–C₇)heterocyclyl group whereintwo adjacent methylene carbons of said —(C₂–C₇)heterocyclyl group arefused to a phenyl or —(C₂–C₅)heteroaryl group; wherein A is optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, cyano, R¹, —NR¹R², —NH(CO)R¹,—NR²(CO)R¹, —(C₁–C₆)alkyl-NR¹R², —(C₁–C₆)alkyl-NH(CO)R¹,—(C₁–C₆)alkyl-NR²(CO)R¹ —NHSO₂R¹, —N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —OR¹, —(C₁–C₆)alkyl-OR¹,—(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²;and said cyclic group A is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR³.
 4. A compound according to claim 1 wherein Ar is amoiety of formula 2:


5. A compound according to claim 1 wherein Ra is selected from the groupconsisting of hydrogen, halogen, hydroxy, —CF₃, and —CN.
 6. A compoundaccording to claim 1 wherein Ar is a moiety of formula 2 and Ra isselected from the group consisting of hydrogen, halogen, hydroxy, —CF₃,and —CN.
 7. A compound according to claim 1 wherein Rb is selected fromthe group consisting of hydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and—(C₂–C₉)heterocyclyl.
 8. A compound according to claim 1 wherein Ar is amoiety of formula 2 and Rb is selected from the group consisting ofhydrogen, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl.9. A compound according to claim 1 wherein Ar is a moiety of formula 2,Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, and Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl.
 10. Acompound according to claim 1 wherein Rc independently represents asubstituent selected from the group consisting of hydrogen, hydroxy,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and (C₂–C₉)heterocyclyl, or two Rcsubstituents may be taken together with the atom to which they areattached to form a cyclic group, —(C₃–C₁₀)-cycloalkyl or(C₂–C₉)-heterocyclyl.
 11. A compound according to claim 1 wherein Ar isa moiety of formula 1 and Rc independently represents a substituentselected from the group consisting of hydrogen, hydroxy, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, -and (C₂–C₉)heterocyclyl, or two Rc substituents maybe taken together with the atom to which they are attached to form acyclic group, —(C₃–C₁₀)-cycloalkyl or (C₂–C₉)-heterocyclyl.
 12. Acompound according to claim 1 wherein Ar is a moiety of formula 2, Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl, and Ra is selected fromthe group consisting of hydrogen, halogen, hydroxy, —CF₃, and —CN.
 13. Acompound according to claim 1 wherein Ar is a moiety of formula 2, Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl, Ra is selected from thegroup consisting of hydrogen, halogen, hydroxy, —CF₃, and —CN, and Rb isselected from the group consisting of hydrogen, —(C₁–C₆)alkyl,—(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl.
 14. A compound accordingto claim 1 wherein A is a suitably substituted —(C₂–C₉)heterocyclylgroup inclusive of the ring nitrogen atom at the juncture between cyclicmoiety A and the C-4 position of the pyrimidine ring of formula I;wherein A is optionally substituted by 1 to 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, —NHSO₂R¹,—N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹), —(C₁–C₆)alkyl(NHSO₂)(R¹),—(C₁–C₆)alkyl(N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹,SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²; and said cyclic group A is optionallyinterrupted by one to three elements selected from the group consistingof —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR³.
 15. A compound accordingto claim 1 wherein A is a suitably substituted —(C₂–C₇)heterocyclylgroup wherein two adjacent methylene carbons of said—(C₂–C₇)heterocyclyl group are fused to a phenyl or —(C₂–C₅)heteroarylgroup; wherein A is optionally substituted by 1 to 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,—NHSO₂R¹, —N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹),—(C₁–C₆)alkyl(NHSO₂)(R¹), —(C₁–C₆)alkyl(N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²;and said cyclic group A is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR³.
 16. A compound according to claim 1 wherein Ar is afused ring system selected from the group consisting of:


17. A compound according to claim 1 wherein Ar is a fused ring systemselected from the group consisting of:

Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, and Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(G2–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl.
 18. A compound accordingto claim 1 wherein Ar is a fused ring system selected from the groupconsisting of:

Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, and Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl; and A is a suitablysubstituted —(C₂–C₉)heterocyclyl group inclusive of the ring nitrogenatom at the juncture between cyclic moiety A and the C-4 position of thepyrimidine ring of formula I; wherein A is optionally substituted by 1to 3 substituents independently selected from the group consisting ofhalogen, hydroxyl, —NHSO₂R¹, —N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹),—(C₁–C₆)alkyl(NHSO₂)(R¹), —(C₁–C₆)alkyl(N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²;and said cyclic group A is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR³.
 19. A compound according to claim 1 wherein Ar is afused ring system selected from the group consisting of:

Ra is selected from the group consisting of hydrogen, halogen, hydroxy,—CF₃, and —CN, Rb is selected from the group consisting of hydrogen,—(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, and —(C₂–C₉)heterocyclyl, and Rcindependently represents a substituent selected from the groupconsisting of hydrogen, hydroxy, —(C₁–C₆)alkyl, —(C₃–C₇)cycloalkyl, -and(C₂–C₉)heterocyclyl, or two Rc substituents may be taken together withthe atom to which they are attached to form a cyclic group,—(C₃–C₁₀)-cycloalkyl or —(C₂–C₉)-heterocyclyl, and A is a suitablysubstituted —(C₂–C₇)heterocyclyl group wherein two adjacent methylenecarbons of said —(C₂–C₇)heterocyclyl group are fused to a phenyl or—(C₂–C₅)heteroaryl group; wherein A is optionally substituted by 1 to 3substituents independently selected from the group consisting ofhalogen, hydroxyl, —NHSO₂R¹, —N(R²)(SO₂)(R¹), —(C₁–C₆)alkyl(SO₂)(R¹),—(C₁–C₆)alkyl(NHSO₂)(R¹), —(C₁–C₆)alkyl(N(R²)(SO₂)(R¹),—(C₁–C₆)alkyl-OSO₂R¹, —O—SO₂R¹, —SO₂R¹, SO₂NH₂, SO₂NHR¹ and —SO₂NR¹R²;and said cyclic group A is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR³.
 20. A compound selected from the group consistingof:N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-yl}-methanesulfonamide;5-[4-(4-Methanesulfonyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-ylmethyl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-ylmethyl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(S)-ylmethyl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-yl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(S)-yl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(S)-yl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(R)-yl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-3(R)-ylmethyl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-piperidin-4-ylmethyl}-methanesulfonamide;N-{1-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-yl}-methanesulfonamide;N-Methyl-N-{4-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-morpholin-2-ylmethyl}-methanesulfonamide;N-Methyl-N-{1-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-pyrrolidin-3(R)-yl}-methanesulfonamide;N-Methyl-N-{1-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-yl]-azetidin-3-ylmethyl}-methanesulfonamide;5-[4-(4-Methanesulfonyl-[1,4]diazepan-1-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;and5-[4-(1,3-Dihydro-isoindol-2-yl)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one.21. A method for the treatment of breast cancer in a mammal comprisingadministering to said mammal an amount of a compound of claim 1 that iseffective in treating breast cancer.
 22. A pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.